POS0335 EXOSOMES TRANSMIT DAMAGE SIGNALS FROM INFRAPATELLAR FAT PAD AND EXACERBATE CHONDROCYTE SENESCENCE IN OSTEOARTHRITIS
Authors: Y. Cao, J. Ruan, J. Kang, X. Nie, G. Ruan, Z. Zhu, W. Han, S. Tang, C. Ding
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Infrapatellar fat pad (IPFP) is closely associated with the development and progression of knee osteoarthritis (OA)<sup>[1-5]</sup>, but the underlying mechanism remains unclear. <h3>Objectives</h3> This study aims to investigate the role and regulatory mechanisms of osteoarthritic infrapatellar fat pad (IPFP) tissue-derived exosomes (IPFP-Exos) in chondrocytes senescence and osteoarthritis (OA) progression. <h3>Methods</h3> The IPFP were collected from late-stage OA patients with knee arthroplasty. The role of endogenous osteoarthritic IPFP-Exos was measured in human IPFP explants coculturing with chondrocytes and mice post-traumatic OA models induced by destabilization of the medial meniscus (DMM) surgery with GW4869 or vehicle treatment. Extraction of IPFP tissue exosomes was performed by ultracentrifugation. Chondrocytes degradation and cellular senescence were assessed by qRT-PCR, western blotting, alcian blue and toluidine blue staining, immunofluorescence and senescence-associated beta-galactosidase staining, respectively. MiRNA sequencing was employed in IPFP-Exos to explore its cargoes. Luciferase reporter assay was used to reveal the interaction between exosomal miRNAs and their downstream mRNA target. <h3>Results</h3> Osteoarthritic IPFP tissue could secret exosomes and delivery them into articular chondrocytes. Inhibition of endogenous osteoarthritic IPFP-Exos significantly alleviated cartilage distruction. Functional assays <i>in vitro</i> demonstrated that IPFP-Exos significantly promoted chondrocyte extracellular matrix (ECM) catabolism and cellular senescence. Moreover, further experiments demonstrated that IPFP-Exos induced ECM degradation in human and mice cartilage explants and aggravated the progression of experimental OA mice model. Mechanistically, highly enriched let-7b-5p and let-7c-5p in IPFP tissue-derived exosomes were essential to mediate detrimental effects by directly decreasing senescence negative regulator, lamin B receptor (LBR). Notably, intra-articular injection of antagomirs inhibiting let-7b-5p and let-7c-5p in mice increased LBR expression, suppressed chondrocyte senescence and ameliorated the progression of experimental OA model. <h3>Conclusion</h3> This study highlights the function and mechanism of the IPFP-Exos in the progression of OA. Targeting IPFP-Exos cargoes of let-7b-5p and let-7c-5p provide a potential prevention strategy for OA. <h3>References</h3> [1]Pan F, Han W, Wang X, Liu Z, Jin X, Antony B, Cicuttini F, Jones G, Ding C. A longitudinal study of the association between infrapatellar fat pad maximal area and changes in knee symptoms and structure in older adults. <i>Ann Rheum Dis</i>. 2015;74:1818-1824. DOI: 10.1136/annrheumdis-2013-205108. [2]Han W, Aitken D, Zhu Z, Halliday A, Wang X, Antony B, Cicuttini F, Jones G, Ding C. Signal intensity alteration in the infrapatellar fat pad at baseline for the prediction of knee symptoms and structure in older adults: a cohort study. <i>Ann Rheum Dis</i>. 2016;75:1783-1788. DOI: 10.1136/annrheumdis-2015-208360. [3]Han W, Aitken D, Zhu Z, Halliday A, Wang X, Antony B, Cicuttini F, Jones G, Ding C. Hypointense signals in the infrapatellar fat pad assessed by magnetic resonance imaging are associated with knee symptoms and structure in older adults: a cohort study. <i>Arthritis Res Ther</i>. 2016;18:234. DOI: 10.1186/s13075-016-1130-y. [4]Wang K, Ding C, Hannon MJ, Chen Z, Kwoh CK, Lynch J, Hunter DJ. Signal intensity alteration within infrapatellar fat pad predicts knee replacement within 5 years: data from the Osteoarthritis Initiative. <i>Osteoarthritis Cartilage</i>. 2018;26:1345-1350. DOI: 10.1016/j.joca.2018.05.015. [5]Zhou Z, Tang S, Nie X, Zhang Y, Li D, Zhao Y, Cao Y, Yin J, Chen T, Ruan G, et al. Osteoarthritic infrapatellar fat pad aggravates cartilage degradation via activation of p38MAPK and ERK1/2 pathways. <i>Inflamm Res</i>. 2021;70:1129-1139. DOI: 10.1007/s00011-021-01503-9. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests:</h3> None declared.